Following virus infection, cells may undergo apoptosis to prevent further virus spread in the host. This has spurred viruses to evolve counteracting mechanisms to prevent host cell death, and during latent infection these factors may contribute to the development of cancer. This includes multiple cancers associated with Epstein-Barr virus (EBV), in particular Burkitt's lymphoma (BL).
Apoptosis and cell survival are regulated by the homeostatic balance of B cell lymphoma-2 (Bcl-2) family proteins (reviewed in (Martinou and Youle, 2011)), which fall in to three classes. The ‘executioners’, Bak and Bax, initiate apoptosis by increasing mitochondrial outer membrane permeability and facilitating the release of mitochondrial cytochrome c to the cytosol, which activates downstream signaling. Six human pro-survival Bcl-2 proteins (Bcl-2, Bcl-XL, Bcl-B, Mcl-1, Bcl-w and Bfl-1) inhibit this process. Counterbalancing these are numerous pro-apoptotic BH3-only proteins (BOPs), including Bim. These factors share an approximately 26 residue Bcl-2 homology 3 (BH3) motif, an amphipathic α-helical element which binds a hydrophobic groove on the surface of the canonical Bcl-2 fold. Cellular stresses activate pro-apoptotic BOPs, which bind and inhibit pro-survival Bcl-2 members, and directly interact with Bak and Bax to favor mitochondrial permeabilization. Conversely, pro-survival Bcl-2 proteins dampen apoptotic triggers and enhance chemoresistance by sequestering BOPs or directly inhibiting Bak and Bax. Increased expression of pro-survival Bcl-2 proteins is a common feature of many cancers.
Epstein-Barr virus encodes a pro-survival Bcl-2 homologue, BHRF1, which prevents lymphocyte apoptosis during initial infection by sequestering pro-apoptotic BOPs (especially Bim), and interacting directly with the executioner Bak (Desbien et al., 2009; Kvansakul et al., 2010) (Altmann and Hammerschmidt, 2005) (Henderson et al., 1993). Even though BHRF1 is under the control of an early lytic cycle promoter, low levels of constitutive expression have been observed in some cases of EBV-positive BL when the virus is latent, and it has been speculated that BHRF1 may be a necessary viral factor for lymphomagenesis (Kelly et al., 2009; Leao et al., 2007; Watanabe et al., 2010).